Synthesis of Tetrahydro-1,4-Benzodiazepine-2-ones on Hydrophilic Polyamide SynPhase Lanterns

Abstract

Solid-phase synthesis is greatly dependent on the solid support. Here, we report the use of a new hydrophilic grafted surface on SynPhase lanterns in solid-phase organic chemistry. A convenient and facile solid-phase synthesis of disubstituted 1,4-benzodiazepine-2-ones on polyamide SynPhase lanterns is described. The key step of the synthesis involved a reduction-cyclization of a nitroaryl methyl ester with a mixture of tin(II) chloride dihydrate and ammonium acetate in water and ethanol at elevated temperature to give the desired target compounds. A library of 21 disubstituted 1,4-benzodiazepine-2-ones was prepared.

Synthesis of an 8‐Benzyl‐4‐(p‐substituted‐benzyl)‐1,4,8‐triazaspiro[4.5]decan‐2‐one Library on SynPhase TMLanterns

“…The side-chain of N-substituted amino acid amides constituting another site of diversity (position 3 of the spiroimidazolidinone system), a collection of eight amino acid amides (chemset 12, Table 3) and N-benzyl-4-piperidone. For synthesizing this library, we chose SynPhase TM Rink polyamide Lanterns [7] as solid support and the TranSort method as tagging system [8]. This identification method consists in attaching radiofrequency tags, called TranStems, to the Lantern allowing to track the reaction history of each Lantern and to identify the individual final expected compounds.…”

Solid-Phase Synthesis of Seven-Membered Heterocycles with Two Nitrogen Atoms

“…This method was also applicable to cyclic amino acid esters, such as proline methyl ester, to give structurally constrained tricyclic compounds. The same approach was later utilized by Ede to synthesize the benzodiazepines 80 on Synphase lanterns [36]. However, in contrast to Lou's procedure, the N 4 -alkylation was performed with alkyl halides in the stage of linear intermediates 77.…”

Solid-Phase Synthesis of Tetrahydro-1,4-benzodiazepine-2-one Derivatives as a β-Turn Peptidomimetic Library

“…Recently, biologically active benzothiazepines with important residues at the C-7 position have been reported as tumor necrosis factor R converting enzyme (TACE) inhibitors, showing selective and potent activities against porcine TACE. 14 Although there have been a number of library syntheses of benzodiazepines since Ellman's group developed a solidphase synthesis of 1,4-benzodiazepines in the early 1990s, 15 there have been few publications of solid-phase synthesis of tetrahydro-1,4-benzodiazepin-2-ones, 16,17 and most benzodiazepine libraries have limited diversity on the benzene ring, since they use the benzene moiety to link to the resin or they introduced the benzene moiety in building blocks such as anthranilic acids to give diversity. 18 Here, we report a successful parallel solid-phase synthesis of a tetrahydrobenzo[e] [1,4]diazepin-2-one library with three points of diversity, including the C-7 position, with alkoxy derivatizations, as β-turn peptidomimetics.…”